ArticleAnnals of oncology : official journal of the European Society for Medical Oncology2017
Role of proton-coupled folate transporter in pemetrexed resistance of mesothelioma: clinical evidence and new pharmacological tools.
Article in Annals of oncology : official journal of the European Society for Medical Oncology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 45 citations in OpenAlex.
- Transporters in vitamin uptake and cellular metabolism: impacts on health and disease.Life metabolism · 2025Review
- The Roles of Exosomes in Anti-Cancer Drugs.Cancer medicine · 2025Review
- An Overview of Cellular and Molecular Determinants Regulating Chemoresistance in Pleural Mesothelioma.Cancers · 2025Review
- The role of l-leucovorin uptake and metabolism in the modulation of 5-fluorouracil efficacy and antifolate toxicity.Frontiers in pharmacology · 2024Article
- Discovery of Tumor-Targeted 6-Methyl Substituted Pemetrexed and Related Antifolates with Selective Loss of RFC Transport.ACS medicinal chemistry letters · 2023Article
- The Influence of Mitochondrial Energy and 1C Metabolism on the Efficacy of Anticancer Drugs: Exploring Potential Mechanisms of Resistance.Current medicinal chemistry · 2023Review
- Biology and therapeutic applications of the proton-coupled folate transporter.Expert opinion on drug metabolism & toxicology · 2022Article
- The evolving biology of the proton-coupled folate transporter: New insights into regulation, structure, and mechanism.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2022Review
- Folate Transport and One-Carbon Metabolism in Targeted Therapies of Epithelial Ovarian Cancer.Cancers · 2021Review
- Review
- Uncovering cancer vulnerabilities by machine learning prediction of synthetic lethality.Molecular cancer · 2021Article
- Article
- Discovery of 6-substituted thieno[2,3-d]pyrimidine analogs as dual inhibitors of glycinamide ribonucleotide formyltransferase and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase in de novo purine nucleotide biosynthesis in folate receptor expressing human tumors.Bioorganic & medicinal chemistry · 2021Article
- Folate transporter dynamics and therapy with classic and tumor-targeted antifolates.Scientific reports · 2021Article
- Therapeutic Targeting of Mitochondrial One-Carbon Metabolism in Cancer.Molecular cancer therapeutics · 2020Review
- Impact of hypoxia on chemoresistance of mesothelioma mediated by the proton-coupled folate transporter, and preclinical activity of new anti-LDH-A compounds.British journal of cancer · 2020Article
- RX-3117 (Fluorocyclopentenyl-Cytosine)-Mediated Down-Regulation of DNA Methyltransferase 1 Leads to Protein Expression of Tumor-Suppressor Genes and Increased Functionality of the Proton-Coupled Folate Carrier.International journal of molecular sciences · 2020Article
- Combining epigenetic drugs with other therapies for solid tumours - past lessons and future promise.Nature reviews. Clinical oncology · 2020Review
- VARIDT 1.0: variability of drug transporter database.Nucleic acids research · 2020Article
- Metabolic rewiring and redox alterations in malignant pleural mesothelioma.British journal of cancer · 2020Review
Corrections and comments
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Authors and funding
14 authors at 8 institutions in 4 countries.
Funding
Abstract
backgroundThymidylate synthase (TS) has a predictive role in pemetrexed treatment of mesothelioma; however, additional chemoresistance mechanisms are poorly understood. Here, we explored the role of the reduced-folate carrier (RFC/SLC19A1) and proton-coupled folate transporter (PCFT/SLC46A1) in antifolate resistance in mesothelioma. PATIENTS AND
methodsPCFT, RFC and TS RNA and PCFT protein levels were determined by quantitative RT-PCR of frozen tissues and immunohistochemistry of tissue-microarrays, respectively, in two cohorts of pemetrexed-treated patients. Data were analyzed by t-test, Fisher's/log-rank test and Cox proportional models. The contribution of PCFT expression and PCFT-promoter methylation to pemetrexed activity were evaluated in mesothelioma cells and spheroids, through 5-aza-2'-deoxycytidine-mediated demethylation and siRNA-knockdown.
resultsPemetrexed-treated patients with low PCFT had significantly lower rates of disease control, and shorter overall survival (OS), in both the test (N = 73, 11.3 versus 20.1 months, P = 0.01) and validation (N = 51, 12.6 versus 30.3 months, P = 0.02) cohorts. Multivariate analysis confirmed PCFT-independent prognostic role. Low-PCFT protein levels were also associated with shorter OS. Patients with both low-PCFT and high-TS levels had the worst prognosis (OS, 5.5 months), whereas associations were neither found for RFC nor in pemetrexed-untreated patients. PCFT silencing reduced pemetrexed sensitivity, whereas 5-aza-2'-deoxycytidine overcame resistance.
conclusionsThese findings identify for the first time PCFT as a novel mesothelioma prognostic biomarker, prompting prospective trials for its validation. Moreover, preclinical data suggest that targeting PCFT-promoter methylation might eradicate pemetrexed-resistant cells characterized by low-PCFT expression.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.